The mutated ataxia telangiectasia (AT) gene causes a distinctive neurological, immunological and cancer-prone syndromes in homozygotes. Heterozygous carriers of this gene constitute about 1 percent of the general population. The principal investigator and others have generated data that support the hypothesis that these heterozygous carriers are predisposed to breast and other cancers. Prospective clinical data will be continued to be collected from blood relatives in approximately 266 AT families already participating in this study. These will be incorporated with their own detailed retrospective health and mortality data. DNA samples will be collected for as many relatives as possible. The specific AT mutations segregating in these families will be determined as a basis for eventual population-based studies, to evaluate the role of different mutations in disease predisposition, and for use in this study. The AT gene carrier status of each participating relative will be determined through linked haplotypes or direct mutation detection. The excess mortality and disease risk of AT heterozygotes compared to non-carriers will be evaluated by rate ratio analysis of the prospective mortality and disease incidence rates. The statistically powerful unbiased index-test method will be used to estimate the relative risk of the AT heterozygote for specific cancers and ischemic heart disease. The role of environmental factors such as ionizing radiation and smoking will be examined through nested case-control studies. New measures to reduce the mortality and excess disease incidence of AT heterozygotes will be developed based upon the findings of this study.